Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end‐stage kidney disease: A national cohort study

Abstract Background Patients with end‐stage kidney disease (ESKD) are at significantly increased risk for both thrombosis and bleeding relative to those with normal renal function. The optimal therapy of venous thromboembolism (VTE) in patients with ESKD is unknown. Objective To compare the safety and effectiveness of apixaban relative to warfarin in patients with ESKD and acute VTE. Design, Setting and Participants New‐user, active‐comparator retrospective United States population‐based cohort with inverse probability of treatment weighting, using the United States Renal Data System data from 2014 to 2018. We included adults with ESKD on hemodialysis or peritoneal dialysis who were newly initiated on apixaban or warfarin for an acute VTE. Main Outcome and Measures The coprimary outcomes were major bleeding, recurrent VTE, and all‐cause mortality within 6 months of anticoagulant initiation. Secondary outcomes were intracranial hemorrhage and gastrointestinal bleeding. The primary analyses were based on intent‐to‐treat defined by the first drug received and accounted for competing risks of death. Sensitivity analyses included varied follow‐up time, as‐treated analyses, and dose‐specific apixaban subgroups. Results The apixaban and warfarin cohorts included 2302 and 9263 patients, respectively. Apixaban was associated with a lower risk of major bleeding (hazard ratio [HR] 0.81, 95% confidence interval [CI]: 0.70–0.94), intracranial bleeding (HR 0.69, 95% CI 0.48–0.98), and gastrointestinal bleeding (HR 0.82, 95% CI 0.69–0.96). Recurrent VTE and all‐cause mortality were not significantly different between the groups. Conclusion Apixaban was associated with a lower risk of bleeding relative to warfarin when used to treat acute VTE in patients with ESKD on dialysis.


INTRODUCTION
Patients with end-stage kidney disease (ESKD) are at significantly increased risk for both thrombosis and bleeding relative to those with normal renal function, which makes anticoagulation particularly challenging. [1][2][3] Furthermore, patients with ESKD initiating anticoagulation for venous thromboembolism (VTE) are typically hospitalized to receive parenteral heparin when starting warfarin, putting them at risk for hospital-associated complications, including heparin-induced thrombocytopenia. A safe, effective therapy for this high-risk population is needed.
The direct oral anticoagulants (DOACs)-apixaban, dabigatran, edoxaban, and rivaroxaban-have provided options for the management of VTE but have not been extensively evaluated in individuals with ESKD for this indication. Rivaroxaban and dabigatran have been associated with a higher risk of bleeding than warfarin in patients with ESKD who are anticoagulated for atrial fibrillation (AF) in observational studies. 4,5 A small randomized study of reduced dose rivaroxaban (10 mg daily) versus warfarin noted similar rates of major bleeding, stroke, and systemic embolism in this population although it was underpowered to demonstrate noninferiority for these clinically important outcomes. 6 Apixaban may be safer than warfarin [7][8][9] with recent evidence supporting lower bleeding rates in patients with ESKD treated for AF. 10,11 RENAL-AF, an open randomized controlled trial (RCT) of apixaban versus warfarin for atrial fibrillation in patients on hemodialysis was halted prematurely due to slow accrual. Therefore, high-quality RCT data evaluating DOACs for patients with ESKD and AF are lacking. Similarly, the safety and effectiveness of apixaban relative to warfarin in patients with ESKD and acute VTE have not been extensively studied. There is reason to speculate that bleeding risk and risk of recurrent thrombosis could be different in patients with AF compared to VTE treated with apixaban. Patients with VTE are generally treated with higher doses of apixaban (10 mg twice daily for 1 week followed by 5 mg twice daily); in AF, there is no role for doses greater than 5 mg twice daily at treatment initiation, and some patients can be treated with 2.5 mg twice daily, depending on patient factors. 12 In contrast, in VTE, the use of less than 5 mg twice daily-regardless of patient characteristics-is off-label. We sought to characterize recent trends in the use of apixaban to treat VTE in ESKD and evaluate the safety and effectiveness of apixaban compared to warfarin. We hypothesized a lower bleeding risk and similar effectiveness of apixaban when compared to warfarin.

Data source, study design, and population
The United States Renal Data System (USRDS) is a national data system that collects, analyses, and distributes information about chronic kidney disease (CKD) and ESKD in the United States. 13 It includes all available Medicare Parts A, B, and D claims data from affected individuals and supplements this with extensive data provided by dialysis centers. The USRDS includes information about these Medicare beneficiaries' healthcare service use including inpatient and outpatient encounters and outpatient prescription medication use. We used institutional claims, physician/supplier We performed a new-user, active-comparator retrospective cohort study. Patients aged 18 years or greater with ESKD on dialysis, and fee-for-service Medicare as their primary insurance, who were newly initiated on either apixaban or warfarin between January 1, 2014 and June 30, 2018, were eligible for inclusion. We required 6 months of continuous Medicare enrollment in Parts A, B, and D before initiation of anticoagulation for inclusion. For cohort entry, we required a diagnosis of VTE using the International Classification of Disease (ICD)-9 and ICD-10 codes (Supporting Information: Appendix Table 1) from 30 days before to 7 days after the initial prescription for apixaban or warfarin. We excluded patients with a claim indicating AF or who were admitted to hospice within the 6 months prior to anticoagulant initiation. Additionally, we excluded patients with any anticoagulant use (DOAC or warfarin) in the 30 days prior to cohort entry or 60 or more cumulative days of anticoagulant treatment (DOAC, warfarin, unfractionated heparin, or low-molecular-weight heparin) for any diagnosis in the 6 months prior to cohort entry (Supporting Information: Appendix Figure 1). We stratified the population by treatment and characterized the cohorts by age (continuous variable), gender (binary variable), race (Black, White, other), ethnicity (Hispanic, non-Hispanic), eligible for Medicaid (yes/no), calendar year of index medication fill, and duration on dialysis (categorical variable). We tabulated the prevalence of comorbid conditions that are most prevalent in this population and/ or associated with thrombosis or bleeding. These comorbidities were identified using ICD-9 and 10, Healthcare Common Procedure  Table 2). We also extracted information on concurrent medication use, focusing on medications associated with bleeding and thrombosis.

Outcomes and follow-up
All outcomes were prespecified. A primary outcome was major bleeding within 6 months of anticoagulant initiation, defined as either (a) bleeding associated with death, (b) critical site bleeding requiring hospitalization, or (c) bleeding at any site requiring hospitalization with transfusion. 19 We further classified these major bleeding events as fatal or nonfatal. Secondary bleeding outcomes were clinically relevant nonmajor bleeding (defined as critical site bleeds not requiring hospitalizations and noncritical site bleeds requiring hospitalizations but not transfusions), intracranial bleeding, gastrointestinal (GI) bleeding, and the number of transfusion events per patient (Supporting Information: Appendix Table 3). The co-primary outcomes were recurrent VTE and all-cause mortality within 6 months of anticoagulant initiation. Recurrent VTE required a new diagnosis code of VTE in the primary position during a hospitalization beginning more than 21 days after the index anticoagulant prescription.
Follow-up continued until the earliest of disenrollment from Medicare (parts A, B, or D), kidney transplantation, enrollment in hospice, death, or 6 months. A patient was able to contribute multiple clinical outcomes (clinically relevant nonmajor, nonfatal major, and fatal major bleed, recurrent VTE). We counted only a single bleeding event (i.e., the most severe event) and/or thrombotic event for a patient during a given hospitalization.

Statistical analyses
We used descriptive statistics to characterize the study population.
We calculated the percentage of patients with each of the primary outcomes by treatment group. Additionally, we characterized the proportion of the apixaban group that was prescribed the 5 mg tablet strength exclusively, the 2.5 mg (off-label) tablet strength exclusively, or a combination of these two strengths. We calculated the mean daily dose per patient for apixaban users.
The main analyses were based on the intent-to-treat principle, with exposure defined by the medication first prescribed. We generated a propensity score by modeling the probability of treatment with apixaban rather than warfarin for each cohort member using a logistic regression model including all clinical covariates described above. We then weighted the individuals in the cohort using inverse probability of treatment weights (IPTW) after truncating the weights at the 1st and 99th percentiles. The standardized mean difference between the two cohorts is reported for the unweighted and weighted study populations.
The main analysis used the IPTW-weighted population and estimated a subdistribution hazard, and 95% confidence interval (CI), for each outcome, with death considered as a competing risk for bleeding and recurrent VTE outcomes. The hazard ratio (HR) for death was generated with a Cox proportional hazard model. We included an indicator of treatment initiation year in the models to adjust for changing use patterns over time and other secular trends.
To compare transfusion events between the two cohorts, we used Poisson regression by applying IPTW and adjusting for treatment initiation year as well as the length of follow-up.
We generated cumulative incidence and survival curves based on the cumulative incidence functions of major bleeding, clinically relevant nonmajor bleeding, intracranial bleeding, gastrointestinal bleeding, recurrent VTE, and all-cause mortality with direct adjustment (rather than IPTW) for all covariates and adjustment for index year. [20][21][22] We conducted secondary analyses, varying the follow-up time to 3 months and 1 month to learn if the treatment effects varied early in treatment. We also conducted sensitivity analyses using an as-treated rather than intent-to-treat methodology. For the as-treated analysis, discontinuation of the initial treatment (with or without switching to another anticoagulant) defined as more than 30 days without the index medication were censoring events in addition to those included in the intent-to-treat analysis.
We conducted exploratory subgroup analyses using an intent-totreat methodology in which we compared outcomes between the exclusively 2.5 mg and exclusively 5 mg apixaban subgroups, the 2.5 mg apixaban subgroup and warfarin, and the 5 mg apixaban subgroup and warfarin. These subgroup analyses used direct adjustment for comorbidities and concurrent medications, rather than IPTW. We also performed a sensitivity analysis comparing the outcomes between the entire apixaban cohort and the warfarin cohort using direct adjustment rather than IPTW to control for clinical characteristics and concurrent medications.
Analyses were conducted using SAS, version 9.4.

RESULTS
The apixaban and warfarin cohorts included 2302 and 9263 patients, respectively (Supporting Information: Appendix Table 4). The mean age of individuals in the apixaban and warfarin cohorts was 59.8 years (standard deviation [SD] 15.1 years) and 58.3 (SD 15.2). The apixaban and warfarin cohorts were 45.9% and 44.6% White, respectively, and were 55.3% and 54.1% female ( Table 1). The dialysis modality at the index date was hemodialysis for 93.8% and peritoneal dialysis for 6.2%. The groups were similar even prior to weighting and were very well-matched after weighting ( Table 2). The proportion of apixaban users in the study population increased markedly during the study period from 2% in 2014 to 47% in 2018 (Supporting Information: Appendix Figure 2). Half of the patients in the apixaban cohort filled prescriptions exclusively for 5 mg tablets (50.0%), while 40.5% exclusively filled 2.5 mg tablets and 9.5% filled a combination of the two tablet strengths. The mean daily dose per patient for apixaban users was 6.7 mg (SD 3.0 mg).
Major bleeding affected 13.0% of the study population, with rates of 10.3% and 13.7% in the apixaban and warfarin groups, respectively. GI bleeding affected 10.0% of the entire cohort, with rates of 8.6% and 10.4% in the apixaban and warfarin groups ( Table 3).
The mean follow-up time in the 6-month, intent-to-treat analyses ranged from 145 days (clinically relevant nonmajor bleeding) to 163 days (all-cause mortality) (Supporting Information: Appendix Table 5). Rates of major bleeding, recurrent VTE, and all-cause mortality were primary analyses, while intracranial bleeding, GI bleeding, and clinically relevant nonmajor bleeding were secondary analyses. Relative to warfarin, apixaban was associated with a lower ELLENBOGEN ET AL. Similarly, the rates of transfusion events (an exploratory analysis) were not significantly different between the two cohorts (Supporting Information: Appendix Table 6). In the intent-to-treat analysis, including only the first 3 months since initiating therapy, the bleeding outcomes again favored apixaban over warfarin, and the risk of recurrent VTE was lower in the apixaban group (Supporting Information: Appendix Table 7). Within the first month of treatment, only the rate of clinically relevant nonmajor bleeding was significantly lower in the apixaban group (Supporting Information: Appendix Table 8).
When we censored patients after discontinuation of the first assigned medication (as-treated analysis), we found that the bleeding  Note: HR were generated using the intent-to-treat principle, defined by the medication first prescribed. We utilized a propensity score by modeling the probability of treatment with apixaban rather than warfarin for each cohort member using a logistic regression model including all available clinical covariates. We then weighted the individuals in the cohort using IPTW after truncating the weights at the 1st and 99th percentile. Bold values indicates statistically significant at p < 0.05.
Abbreviations: CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; IPTW, inverse probability of treatment weighting; VTE, venous thromboembolism. a Total major bleeding is slightly less than fatal major bleeding and nonfatal major bleeding combined because some patients had a nonfatal major bleeding hospitalization followed by a fatal major bleeding hospitalization.

DISCUSSION
In this retrospective cohort study, we found that the use of apixaban to treat acute VTE in ESKD increased dramatically between 2014 and 2018. In 2018, nearly an equal proportion of patients with ESKD received an apixaban-based and warfarin-based strategy for acute VTE. In our primary analysis, we found that apixaban was associated with lower bleeding compared to warfarin. Additionally, a signal suggesting a lower rate of recurrent VTE for apixaban relative to warfarin (a co-primary analysis) was present. Our findings were generally robust in sensitivity analyses including those that censored patients when they were no longer exposed to the therapies of F I G U R E 1 Cumulative incidence and survival probabilities for outcomes. Cumulative incidence and survival probabilities of prespecified outcomes to 6 months with direct adjustment for all covariates and index year.
interest. Finally, in an exploratory analysis, we found that a relatively large percentage of the apixaban group was given an off-label, lower dose in keeping with prior studies. 23 The US Food and Drug Administration approved apixaban to treat AF in December 2012 and VTE in August 2014. Although the drug is partially renally cleared, there are no recommended dosing adjustments for patients with VTE and renal insufficiency. 12 In patients with AF and ESKD, a retrospective cohort study showed a lower risk of major bleeding, thromboembolism, and mortality among apixaban-treated patients compared to those treated with warfarin. 10 A meta-analysis showed a lower risk of mortality among apixabantreated patients with AF and ESKD compared to warfarin-treated patients. 11 Several studies also suggest the superiority of apixaban for the treatment of VTE relative to other agents. [24][25][26][27] An analysis of data from four commercial claims databases plus Medicare claims found that among patients with CKD, the risks of recurrent VTE, major bleeding, and clinically relevant nonmajor bleeding were lower in apixaban-treated patients than in warfarin-treated patients. 28 Our analysis includes an additional 2 years of Medicare claims data (2017 and 2018) and focuses exclusively on patients with ESKD receiving dialysis. A recently published analysis using USRDS data to compare apixaban and warfarin to treat acute VTE in patients with ESKD also found a lower adjusted hazard ratio of major bleeding but also noted a significantly lower adjusted hazard ratio of recurrent VTE than in our study. 29  during an index hospitalization. We suspect that the majority of patients in the warfarin cohort received an unfractionated heparin infusion as this is a standard of care in patients with ESKD. 34 It is possible that many apixaban-treated patients also received unfractionated heparin. Relatedly, we cannot say with certainty whether patients in the apixaban cohort received the recommended loading dose of 10 mg twice per day for the first 7 days of treatment due to the nature of medication claims data and the fact that there is not a 10 mg tablet (but instead patients take two 5 mg tablets, for a total dose of 10 mg twice per day during the loading period). Also, given our definition of recurrent VTE, any subsequent VTE events that occurred during a prolonged index hospitalization would not be included in the analysis. More generally, claims-based definitions for VTE have been noted to have relatively low positive predictive values. 35 Finally, there is a possibility of unmeasured confounding which is a risk with any study that is not a randomized clinical trial; we could not, for instance, account for over-the-counter aspirin use, although we have no reason to suspect this differed between apixaban and warfarin-treated patients. Similarly, we could not adjust for body mass index differences, aside from including codes for obesity among our covariates. The fact that the two treatment groups were well-matched prior to propensity score adjustment suggests that major residual confounding is unlikely.
These limitations not with standing, we conclude that apixaban was associated with a lower risk of bleeding and similar rates of recurrent VTE and all-cause mortality compared to warfarin when used to treat acute VTE in patients with ESKD.

ACKNOWLEDGMENTS
The authors would like to thank Amanda Bentram, MS, for her administrative assistance. They would also like to thank Hemalkumar